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Flashcards in 1: Drug Metabolism Deck (52):

2 general outcomes of xenobiotic metabolism

1. termination: loss of therapeutic or toxic activity
2. bioactivation: gain in therapeutic or toxic activity


sites of metabolism throughout the body

-GI tract


what does first pass metabolism refer to?

the liver is the first organ perfused by compounds absorbed in the gut (oral compounds) -> go through here before entering the circulation (affects dose needed)


definition of oral bioavailability

fraction of total dose that reaches systemic circulation


4 factors affecting bioavailability

-membrane permeability
-P-glycoprotein efflux
-pre-systemic first pass metabolism (intestinal, hepatic)


two phases of drug metabolism

I: chemical modification/biotransformation to introduce new functional group or expose group for phase II rxns

II: conjugation of polar group with drug (often kills activity)


what is the importance of drug metabolism?

frequently the most important determinant of duration and intensity of drug response
-alters pharmacological activities of drugs
-influences half-life


3 ways to terminate xenobiotic action



2 ways in which metabolism causes bioactivation

-toxification (particularly via phase I rxns)


bioinactivation vs. detoxification

terminology has more to do with intent:
-bioinactivation -> stop action of therapeutic drugs
-detoxification -> elimination of toxicity of a toxin


how does metabolism change drugs to aid in elimination?

increase polarity of the drugs:
-decrease lipid solubility
-increase water solubility



definition of prodrug

drug metabolite(s) may be more active than the parent compound, or the parent may require activation for the biological activity (bioactivation)


example of toxification

polyaromatic hydrocarbons from cigarette smoke: phase I enzymes metabolize them into planar epoxide compounds, which can intercalate into DNA (mutagenic) --> thought to be the basis of carcinogenicity of cigarette smoke


why are most adverse reactions related to drug metabolism idiosyncratic (unpredictable)?

b/c there are many poorly understood factors:
-which proteins react with reactive metabolite?
-which protein modifications lead to toxicity and how?
-many risk factors influence reactive metabolite formation and inactivation


most frequent reason that new therapeutic agents are not approved by FDA?

drug-induced hepatic damage


reactions that occur in phase I metabolism

typically oxidation
-also reduction, hydrolysis


typical enzyme of phase I reactions? what other substrates are necessary?

cytochrome P450 (CYP)
-utilizes NADPH and O2


what happens to the metabolites of phase I reactions? 2 possible outcomes

1. excreted if sufficiently polar
2. functionalized to undergo subsequent phase II rxn


what determines what the substrates will be for the CYP enzymes?

the shape of the protein determines the size/shape of entry and exit access pathways, which therefore determines which substrates will fit and which will not


in the cytochrome P450 system, what enzyme plays the electron transport role? where do the electrons come from?

P450 reductase, utilizing an electron from NADPH


what are the three most important/prevalent CYPs involved in human drug metabolism?



why is it therapeutically important that the CYPs are responsible for so much of drug metabolism?

significant chance for drug-drug interactions during multi-drug treatment --> when metabolized by the same CYP isoform, only one of the two drugs can be metabolized by the same CYP entity at the same time --> increased half-life, which may cause toxicity


describe the catalytic center of the CYPs

-contains an iron-heme cofactor
-iron coordinated to 4 N's of the heme, to 1 thiolate ligand from Cys, and to 1 water molecule (in native state)
-upon reduction, maximal light absorption "soret peak" at 450 nm


describe the reaction mechanism involving the catalytic iron-heme cofactor of the CYP catalytic site

ferric, low spin --> ferric, high spin --> ferrous --> ferric, hydroperoxide --> oxyferryl, compound I --> ferric --> repeat from start


describe 6 reactions catalyzed by CYPs

1. aromatic hydroxylation
2. N-oxidation (add =O onto amine group)
3. N-dealkylation (-CH3 -> -H on an amine)
4. O-dealkylation
5. Sulfoxidation (add =O to the S of an R-S-R')
6. Deamination (add -OH to a C that is also attached to an amine -> unstable -> rearranges into a ketone + releases amine)


what are some intrinsic factors that are important in determining which CYPs can catalyze which metabolic reactions?

-topography of protein binding site
-steric hindrance of the access to the catalytic heme group
-how the ligand binds
-ligand binding affinity
-intrinsic reactivity of chemical group that is in close proximity to the catalytic center
-accessibility of chemical group


what are three factors that determine binding strength?

-coordination strength with heme iron
-hydrophobic contacts with binding site of CYP
-specific contacts (H-bonds) with binding site residues


name two ways in which inhibitors may outcompete for binding sites on CYPs

-molecules with N as 6th iron-coordinating ligand have stronger affinity to the heme iron than molecules that coordinate with O or C atoms
-additional hydrophobic contacts stabilize the ligand-protein binding


does the substrate always have to do the inhibition? explain

no - sometimes the metabolite is the inhibitor rather than the substrate itself


does inhibition inhibit metabolism of all substrates of a specific CYP? give example

not necessarily - different binding site moieties
(inhibitor might block one substrate from binding, but not block another which accesses catalytic site from another entry point/route)

ex: cimetidine inhibits warfarin metabolism of CYP2C, but does not inhibit ibuprofen metabolism


definition of mechanism-based inhibition (MBI)

aka suicide inhibition
-metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues in the binding site -> further metabolism of same or other drug is delayed as CYP needs to be resynthesized


definition of induction

administration of one drug causes increase in the rate of an enzyme/induces transcription of more CYP genes -> means you could lower efficacy of that drug or another drug metabolized by the induced enzyme b/c it will now be metabolized faster

ex: rifampin is an inducer of alfentanil (opiod analgesic drug)


what is the significance of induction?

-reduced plasma concentrations of drug
-increased toxicity if reactive metabolites are formed


describe the molecular basis of induction

drug or substance binds with nuclear receptor -> receptor dimerizes -> enters nucleus -> induces transcription of new CYPs


examples of induction by bile acids, xenobiotics, and fatty acids

bile acids --> VDR, PXR---(each induces all of the following)--> CYP2A, CYP2B, CYP2C, CYP3A
bile acids --> FXR --> CYP3A, CYP7A1

xenobiotics --> CAR, PXR --(each induces all of the following)--> CYP2A, CYP2B, CYP2C, CYP3A

fatty acids --> PPARa --> CYP4A, CYP7A1


example of how induction can lead to genotoxicity/carcinogenicity

CYP1A1 metabolizes PAH, so if CYP1A1 is induced --> increase reactive planar epoxide production -> increase intercalation of epoxides into DNA -> increased formation of adducts --> toxicity


definition of drug-drug interactions (DDI)

when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food, or chemical


what percent of all drug-drug interactions involve CYPs?

about 50%


what is the significance of drug-drug interactions?

adverse drug reactions, in particular for:
-drugs with high first-pass metabolism (low bioavailability)
-narrow therapeutic indices
-steep dose-response relationships
-multidrug therapies


what is an example of how drug-drug interactions can be beneficial?

lopinavir and ritonavir (HIV protease inhibitors)

lopinavir: substrate of CYP3A4, low bioavailability
ritonavir: inhibitor of CYP3A4, higher bioavailability

combination therapy (Kaletra) gives you higher oral bioavailability of lopinavir so that it is more effective


name the most well-known food-drug interaction

grapefruit inhibits CYP3A4 b/c it contains:
-bergamottin (MBI)
-6',7'-dihydroxybergamottin (MBI)
-naringin (inhibitor of CYP3A4)


name 6 other phase I enzymes

-flavin-containing mono-oxygenase
-alcohol DH
-epoxide hydrolase


describe phase II drug metabolism

these rxns couple drug or activated drug (by phase I rxns) with conjugates (typically polar groups) --> conjugate is more water soluble and less lipid soluble --> significant increase in urinary excretion

typically bioinactivates and detoxifies (but exceptions)


list two exceptions to the idea that phase II metabolism typically bioinactivates and detoxifies compounds

1. bioactivation: morphine --> 6-glucuronide
2. toxification: carcinogenicity, allergic rxns


name the most dominant phase II enzyme

UGTs = uridine 5'-diphosphate [UDP]-glucuronosyl transferases


why are UGT's the most dominant phase II enzyme?

-readily available supply of glucose and UTP in liver -> will react in 4 enzymatic rxns (using ATP, NAD) to uridine diphosphate glucuronic acid (UDPGA)
-many fxnal groups can form glucuronide conjugates
-O-glucuronidation (-COOH, -OH)
-N-glucuronidation (-NH2)
-S-glucuronidation (-SH)


how can phase I metabolites be further metabolized by UGI without a long path between both reactions?

have UGT and P450 spatially co-localized on the ER


name 4 other phase II enzymes besides UGT

-SULT = sulfotransferases
-GST = glutathione S-transferase
-O-, N-, S-methylation by methyltransferases


does age affect drug metabolism? (here, with babies)

yes, it can:
-CYP3A4/7 expression is different pre-natal and post-natal (ex)
-babies have immature UGT systems
-most xenobiotics in maternal circulation cross placenta + only placental efflux pump is P-gp
-can get accumulation of drugs or reactive metabolites --> induction of CYP1A1 --> toxic/carcinogenic metabolites


describe how drug metabolism is changed in the elderly (4 ways)

-drug-drug interactions when taking multiple drugs
-decreased hepatic blood flow --> reduced 1st pass metabolism
-decreased hepatic mass --> slight reduction of some phase I metabolic rxns
-decreased renal blood flow --> decreased renal excretion


can disease affect drug metabolism? examples

-acute and chronic liver diseases can alter hepatic metabolism
-cardiac disease can decrease blood flow to liver -> reduced hepatic clearance


do genetic factors affect drug metabolism?

-poor metabolizers (PM)
-greater potential for drug-drug interactions and AE
-slower bioactivation of prodrug (lower efficacy)
-extensive metabolizers (EM) --> normal
-ultrarapid metabolizers (URM)
-greater rate of drug elimination (lower efficacy)
-greater potential for generating toxic metabolites